tbuckley/cabot-search huggingface dataset:
Abstract 14972: Sestrin2 Prevents Excessive Cardiac Ischemia/Reperfusion Injury by Regulating Unfolded Protein Response
Authors: Xuan Li, Zhen Wang, Jussara M Docarmo, Alexandre A Da Silva, Alan J Mouton, Ana C Omoto, John E Hall
Journal: Circulation (2022)

Introduction: Cardiac ischemia/reperfusion (I/R) can alter redox and calcium homeostasis, causing proteins misfolded or unfolded in endoplasmic reticulum (ER) and activating unfolded protein response (UPR). Appropriate UPR is an adaptive response of the cell, however excessive and prolonged UPR can further deteriorate calcium overload and reactive oxygen species (ROS) overproduction. We have found that Sestrin2 (Sesn2), an endogenous inhibitor of the mammalian target of rapamycin complex 1 (mTORC1) is upregulated after cardiac I/R and lack of Sesn2 in hearts may cause more severe I/R injury. Hypothesis: Sesn2 maintains the ER homeostasis as an adaptive response to attenuate calcium overload and reduce ROS overproduction during myocardial I/R. Methods: Ligation/release of the left anterior descending coronary arteries (LAD) were performed in the C57BL/6J and cardiac specific Sesn2 knock out (Sens2 cKO ) mice to induce myocardial I/R injury. Results: We found that absence of Sesn2 in the hearts increased myocardial infarction by 49.4%, and decreased the systolic function of the heart by 22.9%, compared to wild type (WT) mice. I/R-induced UPR is a time-dependent process, and it reached its peak at 6 hours post reperfusion, but returned to normal after 24 hours of reperfusion in WT mice, however, Sesn2 deficiency resulted in higher and prolonged activation curve of UPR, as well as more myocardial apoptosis, compared to WT mice. We also found that Sesn2 deficiency impaired calcium transient and increased ROS after I/R. Furthermore, the activation of mTORC1 pathway after I/R was also significantly increased and prolonged in Sesn2 cKO hearts. Inhibiting the mTORC1 by rapamycin after I/R reduced myocardial apoptosis in both WT and Sesn2 cKO mice. Conclusions: During I/R, the regulation of the mTORC1 signaling pathway by Sesn2 may be a key factor in maintaining ER homeostasis to reduce cardiac I/R injury.
Abstract 14904: Post-Tavr 30-Day and 90-Day Readmission for Acute Coronary Syndrome - Insight From the National Readmission Database
Authors: Bertrand Ebner, Miguel Martillo, Karla Inestroza, Sukhpreet Kaur, Ian Ergui, michael Albosta, Carlos Vergara-Sanchez, Rafael J Hernandez, Michael Dangl, Jelani Grant, LOUIS VINCENT, Jennifer Maning, Neal Olarte, Rosario Colombo
Journal: Circulation (2022)

Background: Post-transcatheter aortic valve replacement readmissions are increasingly the major focus of quality improvement efforts. Limited data exist about patient post-TAVR readmitted for acute coronary syndrome (ACS). Methods: The National Readmission Sample was queried from 2011-2017 for relevant ICD-9 and ICD-10 codes to identify patients who underwent TAVR who presented with ACS as primary diagnosis after indexed admission for TAVR. We identified 30-day and 90-day readmission rate, characteristics, mortality and in-hospital outcomes. Results: A total of 104,920 patients underwent TAVR. We identified 623 (0.6%) patients with primary diagnosis of ACS post-TAVR. From the patients who presented with ACS, 31% (n=193) and 41% (n=256) occurred within 30 days and 90 days of TAVR, respectively. Within 30-day and 90-day readmission for ACS post-TAVR, average age was 80.2 years and 80.3 years with 66.7% and 61.1% being male, respectively. Baseline characteristics are highlighted on Table 1. Mortality in patients post-TAVR who were readmitted in 30 days and 90 days for ACS was 14.8% and 9.3%, respectively. Conclusions: Although readmissions after TAVR in patients with ACS is relatively low (0.6%), they are associated with higher in-hospital mortality rate than the general population who present with ACS (~7 to 8%) and pose a higher health care burden.
Abstract 14929: Dedicator of Cytokinesis 2 Promotes Atherosclerosis Through Mediating Vascular Inflammation
Authors: Xia Guo, Guoqing Qian, Oluwaseun Adeyanju, Chenxiao Li, Shiyou Chen
Journal: Circulation (2022)

Atherosclerosis is a leading cause of sudden death in patients with cardiovascular disease. It is the major risk factor of coronary artery disease and stroke. The pathophysiological mechanisms of atherosclerosis are complex and there is lack of effective pharmacotherapy for treating atherosclerosis. Dedicator of cytokinesis 2 (DOCK2) plays important roles in immune functions and inflammatory processes. This study aims to explore the role of DOCK2 in the development of atherosclerosis. We generated double knockout (DOCK2-/-;LDLR-/-) mice. The LDLR-/- and DOCK2-/-;LDLR-/- male mice were fed high-fat diet (HFD) for 4 weeks and/or 12 weeks followed by the collection of the aorta and aortic roots. IHC staining showed that DOCK2 was induced in atherosclerotic lesions with increased expression of ICAM-1, VCAM-1, and MCP-1 after HFD for 4 weeks in LDL-/- mice. DOCK2-/-;LDLR-/- mice exhibited a significantly decreased lesion formation compared to LDLR-/- mice after HFD for 12 weeks as shown by Oil-Red O (ORO) staining of the aorta. ORO staining of aortic roots confirmed the reduced lesion size in DOCK2-/-;LDLR-/- mice. DOCK2 deficiency also attenuated the induction of ICAM-1, VCAM-1, and MCP-1 expression by HFD for 12 weeks. These data indicate that DOCK2 is essential for the lesion formation by inducing the adhesion and invasion related molecule expression. Macrophages have been reported to contribute to atherogenesis. Therefore, we evaluated macrophage infiltration in aortic roots of LDLR-/- and DOCK2-/-;LDLR-/- mice fed with HFD for 12 weeks. The data show that there was significantly attenuated macrophage infiltration in aortic roots of DOCK2-/-;LDLR-/- mice compared with that in LDLR-/- mice, as shown by the decreased F4/80-positive cells. Together, our data demonstrate that DOCK2 deficiency attenuates atherosclerosis by alleviating vascular inflammation.
Abstract 14762: Prospective Study Evaluating Management of Hypertension Induced by Anti-VEGF Therapy in Patient With Active Cancer: Preliminary Report From the VEGFHTN Trial
Authors: Adam S Potter, Elizabeth Pierce, Rebecca Caldwell, Gaspar Pina, Praise Oderinde, Efstratios Koutroumpakis, Cezar Iliescu, Anita M Deswal, Nicolas L Palaskas
Journal: Circulation (2022)

Introduction: A nti-neoplastic agents that target vascular endothelial growth factor (VEGF) are known to have cardiovascular toxicities, principally hypertension, with a reported incidence of 21-40% in first-time users. Anti-VEGF induced hypertension can be challenging to control, and significant enough to lead to a dose reduction or discontinuation of the VEGF-targeted therapy, preventing patients from completing their cancer therapy. Methods: A single center prospective cohort of patients with cancer starting anti-VEGF therapy was compared to a retrospective control cohort that was 1:1 matched on gender, race, ethnicity, cancer type, and anti-VEGF therapy. For the prospective cohort, antihypertensive medications were started per an anti-VEGF hypertension algorithm. Elevated blood pressure was defined as consecutive blood pressure readings above 140/90 mmHg and control of blood pressure defined as consecutive readings &lt;140/90 mmHg. Time to development of elevated blood pressure and blood pressure control, number of anti-hypertensive medications needed to control blood pressure were recorded. Results: The prospective cohort consisted of 31 patients which were 1:1 matched to 31 controls who received antihypertensives per standard of care. There were 50% female patients with mean age 61.0 ± 11.9 years. The most common anti-VEGF therapies received included lenvatinib (39%) and bevacizumab (33%) and the most common cancers being treated were kidney (43%) and liver (39%). In the prospective cohort , 24 (77%) developed hypertension greater than 140/90 mmHg compared to 18 (42%) in the control cohort (p=0.174). Of those who developed hypertension the time to control of blood pressure (&lt;140/90mmHg) was improved in the prospective algorithmic approach to anti-VEGF hypertension compared to control (30.5 ± 35.6 days vs 104.9 ± 121.2 days respectively, p=0.007). More anti-hypertensive medications were used in the prospective cohort compared to the matched control (2.6 ± 1.1 vs 1.3 ± 1.0 respectively, p&lt;0.001). Conclusion: A significant proportion of patients receiving VEGF-targeted therapy will develop hypertension. An algorithmic approach to anti-VEGF hypertension leads to earlier blood pressure control.
Abstract 14915: Efficacy of Canagliflozin on Heart Failure Hospitalization Across Diabetes-Specific Risk Scores
Authors: Matthew W Segar, Mohammad S Khan, Kershaw Patel, Muthiah Vaduganathan, Subodh Verma, Javed Butler, Wai Hong W Tang, Ambarish Pandey
Journal: Circulation (2022)

Introduction: Canagliflozin (CAN) vs. placebo (PBO) reduced the risk of hospitalization for heart failure (HHF) in type 2 diabetes. Whether this benefit is uniform across diabetes-specific HF risk scores (WATCH-DM and TRS-HF DM ) is not known. Methods: Using data from the pooled CANVAS and CANVAS-R trials, we stratified participants without prevalent HF by the integer WATCH-DM score derived quintiles (low [≤14] = quintiles 1-2, intermediate [15-19] = quintiles 3-4, high [≥20] = quintile 5) and by the TRS-HF DM score (low [0-1], intermediate [2], high [3-6]). Discrimination and calibration were assessed by Harrell’s C-index and Hosmer-Lemeshow test, respectively. Cox regression models evaluated the effect of CAN on risk of HHF across risk score categories. Results: Among participants without prevalent HF (n = 8,691), CAN vs. PBO reduced the risk of HHF (HR 0.80, 95% CI 0.62-1.03). The WATCH-DM score demonstrated a C-index of 0.70 (95% CI, 0.66-0.73) and no evidence of miscalibration (χ 2 &lt; 20). CAN consistently reduced risk of HHF across WATCH-DM strata (P-intxn = 0.55) with the greatest absolute risk reduction and lowest NNT observed in the highest vs. lowest risk cohort (ARR 4.6% vs. 0.3% and NNT 22 vs. 333) ( Fig. A ). Comparatively, the TRS-HF DM demonstrated a C-index of 0.67 (95% CI, 0.63-0.71) and no evidence of miscalibration (χ 2 &lt; 20). Similar to WATCH-DM, patients in the highest TRS-HF DM risk group derived the greatest absolute risk reduction and lowest NNT (ARR 3.1% vs. -0.3%% and NNT 32 vs. -333) with no differences across strata (P-intxn = 0.17) ( Fig. B ). Conclusions: Both the WATCH-DM and TRS-HF DM can accurately stratify HHF risk in patients with type 2 diabetes and free of HF. Greater absolute risk reductions with CAN vs PBO were observed with higher risk scores.
Abstract 14497: Predictors of Hypertensive Response During Stress Echocardiography
Authors: Sneha Bontu, Siri Kunchakarra, Yevgeniy Brailovsky, Brendan Martin, Valmiki Maharaj, Thriveni Sanagala
Journal: Circulation (2022)

Introduction: Hypertensive response during stress echocardiography has been predominately studied in a healthy population without many comorbidities, unlike the patients for which these tests are indicated. We performed a retrospective study identifying clinical predictors of hypertensive response to both exercise (EXE) and dobutamine (DSE) stress echo. Methods: Retrospective analysis was performed on all patients who underwent stress echo from January 1, 2015 to February 28, 2017 in a tertiary care academic center. Patient demographics, comorbidities, medications and stress echo parameters were evaluated. Patients were characterized based on stress echo completed as EXE or DSE. The primary outcome was hypertensive response. Results: 4670 patients were enrolled: 1238 in the DSE group and 3432 in the EXE group. On multivariable analysis, only resting SBP remained a significant predictor of hypertensive response during DSE (odds ratio (OR) per 20mmHg 3.21, CI 1.57-6.59, p =.001) with an AUC of 0.76. On multivariable analysis, obesity (OR 2.27, CI 1.08-4.8, p =.03), diabetes (OR 3.24, CI 1.22-8.6, p =.02), resting SBP (OR 4.44, CI 2.35-8.38, p &lt;.001), and black race (v. white, OR 4.53, CI 1.62-12.67, p =.004) remained significant predictors of hypertensive response during EXE, with an AUC of 0.82. Conclusions: Elevated resting systolic blood pressure is a strong predictor of hypertensive response in both groups. Controlling resting blood pressure prior to stress testing reduces non-diagnostic test results and improves safety.
Abstract 14969: Transcriptome Signature of Cardiac Fibroblasts in HCM Patients Identifies Novel Drivers Of ECM Remodeling and Pro-Inflammatory Signaling
Authors: Ayman M Ibrahim, Aya Galal, Sarah Halawa, Hasnaa Elfawy, Sara Elshorbagy, Mohamed Roshdy, Fiesal Mohamed, Manar Osman, Mohamed Hosny, Hadir Khedr, Ahmed Moustafa, mona allouba, Yasmine Aguib, Magdi Yacoub
Journal: Circulation (2022)

Introduction: Cardiac fibroblasts (CFs) have a crucial role in ECM remodeling as well as influencing contractility through crosstalk with the cardiomyocytes. There is accumulating evidence that the phenotype of CFs is disease specific. We here investigate the transcriptome signature of CFs in HCM patients and their functional significance. Methods: Primary CFs were isolated from the myectomy specimens of 12 clinically phenotyped HCM patients and 3 controls. RNA library was prepared from the cell isolates, and whole transcriptome sequencing was performed. Differential expression analysis was carried out using the Tuxedo pipeline. Pathway, Gene Ontology (GO) enrichment, and gene network analyses were performed using Ingenuity Pathways Analysis (IPA) and Gprofiler, respectively. Expression of candidate genes was validated using real time PCR, ICC, immunohistochemistry, cytokines profiling and western blotting. Results: Whole transcriptome analysis identified 292 significant differentially expressed genes (DEGs) (pvalue &lt;0.05 threshold) in HCM fibroblasts compared to controls. The DEGs identified with the highest significance were associated with the “Cardiovascular System development and Function” network (1.55e-27 &lt;pvalue&lt; 3.10e-08). The most significant GO terms identified were associated with ECM remodeling, collagen binding, signal receptor binding, circulatory system development and biological adhesion and other relevant processes. The DEGs encompassed gene families such as collagens ( COL7A1, COL17A1, COL21A1, COL15A1 and COL5A3 ), proteases ( MMP9, MMP12, ABI13BP and ADAM19 ), fibulins (FBLN1 and FBLN5), inflammatory and signaling cytokines ( IL6, CCL2, CCL4, CCL11, IGF2, CSF1, FGF16 and FGF2 ), integrins and signaling receptors ( ITGA4, ITGA7, NRP2, SULF2, ADORA2B, CXCR4, FOLR2, PLXNA4 and TREM2 ) and kinases ( DDR1, EFNB2, RGCC, MAPK11, CDKN2B, PTK7, MARCKSL1, ROCK2, MET, TYROBP and KSR1 ). Assessment of candidate genes was further performed by studying their expression patterns in patients’ samples (CFs extracts and tissue sections). Conclusion: Transcriptome signature of CFs derived from HCM identifies new candidate genes and pathways for ECM remodeling, collagen binding and pro-inflammatory signaling.
Abstract 15024: High Concentration Mineral Oil, Corn Oil and Their Constitutive Fatty Acids Do Not Influence Low-Density Lipoprotein (LDL) Oxidation Rates <i>in vitro</i>
Authors: Samuel C Sherratt, Peter Libby, Deepak L Bhatt, Preston Mason
Journal: Circulation (2022)

Introduction: LDL transports dietary long chain fatty acids, constituents that may influence rates of lipid oxidation. Modified LDL promotes foam cell formation during atherosclerosis. The omega-3 fatty acid (n3-FA) eicosapentaenoic acid (EPA) administered as icosapent ethyl (IPE), reduced cardiovascular events in REDUCE-IT compared to mixed n3-FAs in similar high-risk patients (STRENGTH). Some have attributed these discordant outcomes, in part, to placebo choice (mineral versus corn oil) despite very limited oral absorption. We compared the effects of these oils and various FAs on rates of LDL oxidation at supra-pharmacologic doses. Methods: LDL was isolated from human plasma by isopycnic centrifugation, separated into test samples of 100 μg/mL before being incubated at 37°C for 30 min with pharmaceutical grade mineral or corn oil at high concentrations (100 μg/mL) that are comparable to treatment achieved n3-FAs (4 g/d) that have high oral absorption. We also tested FAs contained in these oils, including stearic acid (18:0), arachidic acid (20:0), and linoleic acid (18:2, n-6) as well as ascorbic acid (10 μM) and a water-soluble analog of vitamin E (Trolox, 10 μM) as controls. All samples then underwent copper-induced oxidation (20 μM) monitored by formation of malondialdehyde (MDA). Results: MDA formation increased from 0.28 ± 0.03 to 9.96 ± 0.58 μM ( p &lt;0.001) with vehicle treatment from 0-2 h. Addition of either mineral or corn oil at 100 μg/mL did not significantly influence rates of MDA formation at 2 h (0.02% and 1.93% change vs vehicle, respectively). Nor did we observe any antioxidant activity with constituent FAs stearic acid, arachidic acid, or linoleic acid, FAs with no or two double bonds. As antioxidant controls, ascorbic acid and Trolox both reduced LDL oxidation by 93% and 94% (0.71 ± 0.11 and 0.62 ± 0.04 to 9.96 ± 0.58 μM, p &lt;0.001) after 2 h. Conclusions: Neither mineral nor corn oils affected LDL oxidation even at supra-pharmacologic concentrations. Beyond poor oral absorption, mineral oil and its constituent fatty acids did not affect LDL oxidation, a property related to mechanisms of atherosclerosis.
Abstract 14777: Poor Utilization of Sodium Glucose Cotransporter-2 Inhibitors in Diabetic Patients With Coronary Artery Disease
Authors: Stacy Tsai, Ruth Choi, James T Heywood
Journal: Circulation (2022)

Introduction: Sodium glucose cotransporter-2 inhibitors (SGLT2is) are antihyperglycemic agents found to significantly reduce cardiovascular mortality and heart failure hospitalizations for type 2 diabetics with cardiovascular disease. Despite guidelines from international and national societies recommending the initiation of SGLT2is in this patient population, there are many at-risk patients who have not received this life-saving therapy. We examined this at-risk population at Scripps Health and aimed to address potential barriers to the prescribing of SGLT2is. Methods: SlicerDicer, a data analysis tool in Epic the electronic health record, was utilized to assess population data. With the support of the hospital pharmacy and therapeutics committee, SGLT2is, Empagliflozin and Dapagliflozin, were put on formulary and available for inpatient initiation in April 2022. Results: From January to December 2021 across all Scripps Health campuses, there were 1050 type 2 diabetics with hemoglobin A1c &gt; 5.7%, the majority of whom were treated with antihyperglycemic agents, with GFR &gt; 30 mL/min/1.73m 2 , who underwent PCI for coronary artery disease. Of those patients, more than 75% were not on an SGLT2i. After SGLT2is were available for initiation in the inpatient setting, informational and educational sessions were provided to health care providers, including physicians, nurses, and other allied health professionals. These sessions reviewed current guidelines, how to prescribe the medication, and the side effects to monitor. New workflow was created such that inpatient prescription of SGLT2is would trigger pharmacy support with the submission of prior authorizations and patient counseling. Conclusions: Despite strong guideline recommendations for the use of SGLT2is from cardiology and diabetes societies, a minority of diabetic patients with coronary artery disease, free of contraindications, receive this therapy. This represents an important opportunity to improve patient outcomes. We used a multi-pronged approach to address foreseeable barriers to the prescription of SGLT2is in this at-risk population.
Abstract 14758: Novel Deep Learning Algorithm to Detect Heart Failure With Preserved Ejection Fraction (hfpef) Using Computer Aided Auscultation of Phonocardiogram
Authors: Devanshi N Damani, Shivam Damani, Anoushka Kapoor, Kanchan Kulkarni, Suganti Shivaram, Philip A Araoz, Yogesh Reddy, Barry A Borlaug, Shivaram Poigai Arunachalam
Journal: Circulation (2022)

Introduction: Heart failure with preserved ejection fraction (HFpEF) is an increasingly common clinical syndrome with diagnostic challenges and no effective treatment. The high heterogeneity of HFpEF clinical syndrome demands novel technologies to distinguish from heart failure with reduced ejection Fraction (HFrEF). Currently, invasive hemodynamic exercise testing is performed to evaluate for HFpEF with right heart catheterization. Hypothesis: We hypothesize that a deep learning model can noninvasively detect patients with HFpEF using phonocardiogram (PCG). Methods: Eligible patients undergoing right heart catheterization were recruited after IRB approval. Eko duo stethoscope was used to record simultaneous ECG &amp; PCG at the mitral area on the patients prior to right heart catheterization at baseline. Each recording was 30 seconds in length with a frequency range between 250 - 5000 Hz. R-wave peak detection was performed &amp; beat to beat PCG annotations were performed. The annotated PCG signals were converted into Mel-frequency cepstral coefficients (MFCC) and padded to account for the difference in lengths. Deep Learning model was developed using a Sequential Neural Network with 80% data to train and validate the model and 20% hold out data was used for testing accuracy of the model. Receiver operating curve (ROC) was obtained to estimate area under the curve (AUC) for performance analysis. Results: 42 patients were enrolled with 25 patients diagnosed as HFpEF by right heart catheterization and 17 were reported as controls. 2544 &amp; 1771 individual PCG annotations for HFpEF and controls were used for model training/validation and testing. The model performed reasonably well with accuracy of 0.89, F1 score of 0.88, precision of 0.80 and recall of 0.97 on the test data. ROC was obtained with AUC of 0.94. Conclusions: The results demonstrate the ability of the deep learning model to noninvasively detect HFpEF using PCG. Larger study is needed to validate these findings.